One of the fundamental challenges during the drug development process is extrapolation of the results of in vitro cell-based assays to human responses. The most common form of in vitro cell-based assay is the multiwell plate assay. These assays, however, often give results that are different from in vivo responses, which increase the probability of the drug failing in trials. The main reasons for inaccurate predictions by such multiwell plate assays are that (1) only single cells types are generally tested in a single well, which does not provide complex multi-organ interactions in the human body, and that (2) cells are cultured in 2-D monolayer cell culture inside the wells, and the behavior of cells cultured in 2-D monolayer is vastly different from the behavior of cells in their native tissue, where they are surrounded by various extracellular matrix and neighboring cells.
Microfluidics has been introduced as a way of increasing the efficiency of cell-based tests. Although current microfluidic devices can increase the efficiency of high-throughput screening by automated fluid introduction through microfluidic channels and valves, it is essentially the same concept as the multiwell plate-based assay system; a single cell type is tested in a physiologically non-relevant environment. These current microfluidic devices share the same limitations as multiwell plate systems.
Approximately only one in ten drugs entering clinical trials finally becomes approved during the drug development (I. Kola and J. Landis, Nat. Rev. Drug Discovery, 2004, 3, 711-715). One of the main causes for such a high attrition rate is unforeseen lack of efficacy or toxicity which is not revealed until the later stages of clinical trials. Given the fact that the majority of drug development cost occurs in the later phases of the process (M. Dickson and J. P. Gagnon, Nat. Rev. Drug Discovery, 2004, 3, 417-429), the ability to predict the toxicity of drugs earlier will save a significant amount of resources. The high attrition rate of drug candidates in animal and human trials indicates that the current in vitro systems for studying drug toxicity need to be improved. One major shortcoming of conventional multi-well plate assays is that they lack multi-organ interactions, and therefore cannot reproduce the pharmacokinetics (PK) of drugs, which plays a significant role in determining the pharmacological effect of drugs (J. H. Lin and A. Y. Lu, Pharmacol. Rev., 1997, 49, 403-449).
The potential importance of microfluidic systems in improving the drug development process has been widely recognized (L. Kang, B. G. Chung, R. Langer and A. Khademhosseini, Drug Discovery Today, 2008, 13, 1-13). Microfluidic systems with perfusion cell culture offer a great potential for drug screening in a high-throughput manner (M. S. Kim, W. Lee, Y. C. Kim and J. K. Park, Biotechnol. Bioeng., 2008, 101, 1005-1013; M. S. Kim, J. H. Yeon and J. K. Park, Biomed. Microdevices, 2007, 9, 25-34; M. Y. Lee, R. A. Kumar, S. M. Sukumaran, M. G. Hogg, D. S. Clark and J. S. Dordick, Proc. Natl. Acad. Sci. U.S.A., 2008, 105, 59-63; Z. Wang, M. C. Kim, M. Marquez and T. Thorsen, Lab Chip, 2007, 7, 740-745). Microfluidics can be especially useful for reproducing the PK of drugs, since structures with multiple components such as a metabolizing component (for example, liver) and a target component (for example, tumor) can be connected with fluidic channels for multi-organ interactions. For example, Ma et al. developed a three-layer microfluidic system to test metabolism dependent toxicity of drugs, consisting of a top-layer for feeding drugs, a middle layer with human liver microsomes, and a bottom-layer for cell culture chambers (B. Ma, G. Zhang, J. Qin and B. Lin, Lab Chip, 2009, 9, 232-238). In another study, a hepatocyte-bioreactor was developed to assess hepato-activated transformation of substrates (H. G. Koebe, C. J. Deglmann, R. Metzger, S. Hoerrlein and F. W. Schildberg, Toxicology, 2000, 154, 31-44). These systems successfully demonstrated in vitro observation of metabolism-dependent drug toxicity. However, they are still far from the faithful reproduction of in vivo situations, since they do not capture the true dynamics of drug exposure to the human body.
Although microfluidic systems have a great potential in enhancing the drug development process, actual applications of microfluidic systems in medical or life science area have been limited. One reason for this is because current microfluidic devices require specialized skills for fabrication and operation, which makes it difficult to be used by non-experts (I. Meyvantsson, J. W. Warrick, S. Hayes, A. Skoien and D. J. Beebe, Lab Chip, 2008, 8, 717-724). In addition, microfluidic cell cultures have several issues that need more in depth study, such as biocompatibility of materials, maintenance of sterility, formation of air bubbles, and the effect of shear stress on cells (L. Kim, Y. C. Toh, J. Voldman and H. Yu, Lab Chip, 2007, 7, 681-694). There has been a substantial amount of progress in terms of developing highly complex microfluidic devices for high throughput implementation (S. T. Yang, X Zhang and Y. Wen, Curr. Opin. Drug Discovery Dev., 2008, 11, 111-127), but not much progress has been achieved in terms of simplifying the design and improving the usability of microfluidic systems.
There is therefore a need in the art for an improved microfluidic system that can be used as an in vitro system for studying drug toxicity. There is also a need in the art for a microfluidic system that simulates multi-organ interactions and reproduces the pharmacokinetics (PK) and/or pharmacodynamics (PD) of drugs.
Citation or identification of any reference in Section 2, or in any other section of this application, shall not be considered an admission that such reference is available as prior art to the present invention.